To link to the entire object, paste this link in email, IM or documentTo embed the entire object, paste this HTML in websiteTo link to this page, paste this link in email, IM or documentTo embed this page, paste this HTML in website

DISCOVERY OF A NOVEL HIV-1 INTEGRASE INHIBITOR BINDING SITE:
INSIGHT INTO ENZYME STRUCTURE/FUNCTION AND INHIBITOR DESIGN
by
Laith Qassim Al-Mawsawi
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
December 2007
Copyright 2007 Laith Qassim Al-Mawsawi

HIV-1 integrase (IN) is an essential enzyme for viral replication and the subject of extensive pharmacological research aimed at designing clinically suitable drugs for the treatment of HIV/AIDS. The viral enzyme catalyzes a DNA "cut and paste" reaction resulting in proviral DNA integration into the host cell genome. These reactions are referred to as 3'-processing and strand transfer. Here we present the identification of an inhibitor binding site that represents the first allosteric inhibitor binding site identified for IN. The rational design of drugs targeting this site has the potential to exhibit two simultaneous mechanisms of action: the disruption of IN multimerization and the disruption of the LEDGF/p75-IN interaction, which is an essential IN cellular cofactor for viral replication. The identification of the inhibitor binding site has led to further studies that have uncovered critical biological aspects concerning the relationship between HIV-1 IN structure and function. Our studies have provided evidence of a mechanistic dissimilarity between both IN reactions, although the enzyme utilizes one active site. Additionally, we have uncovered a non-covalent pi electron orbital interaction at the dimeric interface of the viral enzyme that is essential for viral replication. The pi interaction is critical for the strand transfer activity of IN, but not 3'-processing. Lastly, we have demonstrated the biological activity of a LEDGF/p75 derived peptide, the study of which has provided further insight into IN biology.

DISCOVERY OF A NOVEL HIV-1 INTEGRASE INHIBITOR BINDING SITE:
INSIGHT INTO ENZYME STRUCTURE/FUNCTION AND INHIBITOR DESIGN
by
Laith Qassim Al-Mawsawi
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
December 2007
Copyright 2007 Laith Qassim Al-Mawsawi